Unprecedented progression-free survival with first-line lorlatinib in patients with advanced, ALK-positive non-small cell lung cancer: 5-year data from the CROWN trial
Updated results of the randomised, phase III CROWN study demonstrate that the median progression-free survival (PFS) of advanced ALK-positive non-small cell lung cancer (NSCLC) patients who were treated with first-line lorlatinib was still not reached after 5 years of follow-up. This represents the longest PFS ever reported with a targeted therapy in this setting. Furthermore, these results were coupled with a pronounced protection from intracranial progression.
Study design
In the randomised, phase III CROWN trial, 296 patients with treatment-naïve stage IIIB/IV ALK-positive NSCLC were randomly assigned to receive lorlatinib (100 mg once daily) or crizotinib (250 mg twice daily). The primary endpoint of the study was PFS by blinded independent central review (BICR), with secondary objectives including overall survival (OS) and intracranial efficacy (i.e., intracranial response rate, intracranial time to progression). At the planned interim analysis after 18.3 months of median follow-up, lorlatinib was shown to be associated with a significant benefit in PFS by BICR with a hazard ratio (HR) of 0.28 (95%CI: 0.19-0.41). In a subsequent analysis after 3 years of median follow-up, this PFS benefit was confirmed with a median PFS that was not reached for lorlatinib as compared to 9.3 months with crizotinib (HR[95%CI]: 0.27[0.18-0.39]). During ASCO 2024, updated results of this trial were presented after a median follow-up of 60.2 and 55.1 months in the lorlatinib and crizotinib arm, respectively.
Unprecedented PFS result with first-line lorlatinib
At 60.5 months of median follow-up, the median PFS for patients treated with lorlatinib was still not reached as compared to 9.1 months for crizotinib. This translates into a 81% lower risk for disease progression or death for patients treated with lorlatinib compared to crizotinib (HR[95%CI]: 0.19[0.13-0.27]). At the 5-year landmark, 60% of lorlatinib-treated patients was alive and free of progression as compared to 8% in the crizotinib arm. This highly significant benefit in PFS with lorlatinib was seen across all investigated subgroups, with a very pronounced benefit in patients with baseline brain metastases. In patients with baseline brain metastases, the HR for PFS was reported at 0.08 in favour of lorlatinib (95%: 0.04-0.19), with a corresponding PFS rate of 53% and 0% for patients treated with lorlatinib and crizotinib, respectively (63% vs. 10% in patient without brain metastases; HR[95%CI]: 0.24[0.16-0.36]). Of the patients who received lorlatinib, 92% proved to be free from intracranial progression after 5 years of follow-up as compared to 21% in the crizotinib arm (median: not reached vs. 16.4 months; HR[95%CI]: 0.06[0.03-0.12]). Importantly, this time to intracranial progression was significantly longer with lorlatinib both in patients with (HR[95%CI]: 0.03[0.01-0.13]) and without (HR[95%CI]: 0.05[0.02-0.13]) brain metastases at baseline.
Grade ≥3 adverse events (AEs) were reported in 77% of patients treated with lorlatinib, with a 44% incidence of serious AEs. The main contributors to this high rate of grade ≥3 AEs were hypertriglyceridemia (25%), weight increase (23%), hypercholesterolemia (21%) and hypertension (12%). AEs led to a dose reduction in 23% of patients, with a temporary and permanent treatment discontinuation in 62% and 11% of patients, respectively. Importantly, a dose reduction during the first 16 weeks of lorlatinib did not have a detrimental impact on the efficacy of lorlatinib.
Conclusions
After 5 years of follow-up in the CROWN trial, the median PFS was still not reached with lorlatinib, with a 5-year PFS rate of 60%. In addition, the probability of being free of intracranial progression at 5 years was 92%. This PFS corresponds to the longest PFS ever reported with a targeted therapy in advanced NSCLC. As such, these data indicate that first-line lorlatinib provides an unprecedented improvement in outcome for patients with advanced ALK-positive NSCLC.
Reference
Solomon B, et al. Lorlatinib vs crizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study. Presented at ASCO 2024; Abstract LBA8503.
